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Titanium-Promoted Enantioselective Oxidation of Thioethers and Synthetic Applications
L.I. Simandi (Editor), Dioxygen Activation and Homogeneous Catalytic Oxidation 0 1991 Elsevier Science Publishers B.V., Amsterdam
385
Titanium-Promoted Enantioselective Oxidation of Thioethers and Synthetic Applications V. Conte, F. Di Furia, G. Licini, G. Modena and G. Sbampato Centro di Studio sui Meccanismi di Reazioni Organiche del CNR, Dipartimento di Chimica Organica dell'universita', via Marzolo, 11-35131Padova, Italy.
Abstract
The recent results of our studies on the asymmetric oxidation of alkyl and aryl thioethers by the Ti(IV)/(+)-diethyltartrate/alkylhydroperoxide reagent developed in our laboratories will be presented and their relevance in the understanding of the factors affecting the enantioselectivity of the process and in the synthesis of chiral synthons briefly discussed. A preliminary discussion on the structure of the reactive complex will also be presented.
The discovery by Sharpless of the titanium-diethyltartrate-t-butylhydroperoxide reagent for the enantioselective oxidation of allylic alcohols 111 opened a new era in the field of asymmetric synthesis. Much work and thought have been dedicated by Sharpless himself 123 and by others [31 to the understanding of the origin of the exceptional enantioselectivityof the reagent and to the development of a reasonable structure-selectivity relationship. The Sharpless catalyst precursor, where the Ti-DET ratio is 1:1, is inefficient in the asymmetric S-oxidation. However, quite effective modifications of it have been independently discovered by the Kagan's group 141 and by ourselves [51. They have, respectively,the composition Ti:DETH,O= 1:2:1 and Ti:DET=1:4. We deem it worthwhile to elaborate hrther on the structure-reactivity relationship of these systems before presenting our most recent findings in this area. The titanium alkoxides, which have the minima formula Ti(OR),, are coordinatively unsaturated species which tend, in the absence of other neutral ligands, to strongly associate either in the liquid or in the solid state [6]. As an example, Figure 1,based on x-ray data, shows a structure where each titanium atom by extensive oxobridging reaches the hexacoordination [6bl, i.e. the most
386
Figure 1. X-ray structure of Ti(OEt),. 8 = EtO frequent coordination state for Ti(IV). On the other hand, bulky, negatively charged ligands may stabilize lower coordination numbers, e.g. Ti(EtO), is present as pentacoordinate trimer in the liquid state [6dl whereas Ti(t-BuO), and Ti(t-Am), are tetrahedral monomeric species. Some titanium complexes with coordination number higher than six have also been described [2a,61. The system becomes more complicated when together with the alkoxy groups, the ligand contains other neutral centers. In this case the intramolecular coordination of such centers, e.g. the carbonyl of the carboxylate moiety in DET may successfully compete with that of external nucleophiles. Sharpless, on the basis of extensive studies [21, suggested that in his system the catalyst is the species 2, i.e. the dimer formed by association of two pentacoordinate monomers through two oxobridges. In fact, the monomer might reach the hexacoordination only by bonding the second carboxylate group at the expenses of a rather severe distortion. An alternative dimeric structure 3 has also been taken into consideration. In the latter, each Ti might easily reach the hexacoordination via bonding both carboxylate groups although other evidence indicates that the pentacoordination is maintained [2,3b].
0-i-R
a
2
387
It has been also suggested that all the oxygens in 2 are equivalent because of a fluxional equilibrium, likely uia 3. At any rate, one might argue that the titanium species tend to reach the hexacoordination wherever possible even at the expense of a corresponding entropic loss. Along this line we may anticipate some further complications arising from the reaction of the catalyst with the reagents to form the activated complex. Upon additions of the allylic alcohol, one or more of the iso-propoxy groups may be displaced without major modifications of the structure of the complex. However, when the hydroperoxide is added, some significant structural changes are expected because of the bidentate nature of the oxidant. As a matter of fact, in the transition state the hydroperoxide must be bicoordinate to the metal through both peroxo oxygens [71. As a consequence, the DET-alkoxohydroperoxotitanium complex might reach the hexacoordination without dimerization. Alternatively, the dimeric structure might be preserved, by removal of the carboxylate ligand. Although, it is not easy to distinguish between the two alternatives presented above, it may be u s e l l to recall that Corey [3cl has recently suggested that the coordination of the hydroperoxide has a depolimerizing effect on the titanium complex. Whether the subsequent dissociation into ion pairs, as suggested, or two neutrals takes place is not relevant in this context. Independently of the structure of the activated complex in the Sharpless oxidation, either monomeric or dimeric, it is nevertheless possible to propose a rationale for the modifications of the reagent itself which allow the enantioselective oxidation of thioethers. In fact, since such substrates are too weak ligands toward titanium 181 to behave as the allylic alcohols do, they will not displace the iso-propoxygroups in the titanium catalyst. Such groups will be displaced by the hydroperoxide leading either to two diastereoisomeric monoperoxides o r to a diperoxide with the two peroxo groups in diastereotopic positions. It is not surprising that either the mixture of the two monoperoxides or the diperoxide are not efficient enantioselective oxidants. Indeed the Sharpless reagent oxidizes alkyl or aryl thioethers without any significant enantioselectivity, even though it can asymmetrically oxidize p-hydroxy tertiary amines to the corresponding N-oxides [9] and, less efficiently, phydroxythioethers [lo]. This is likely due to the fact that such substrates may act, in some way, like the allylic alcohols as far as the coordination to the metal is concerned. The two modifications of the Sharpless reagent proposed by Kagan (addition of one equivalent of water) [41 and by ourselves (large excess of DET) [5], independently of how they have been conceived, have in common the presence of reagents able to displace either one or both iso-propoxy ligands. This eliminates the problem mentioned above of forming peroxocomplexes rather inefficient as asymmetric oxidants. Even in the absence of direct physical evidence, we may argue that under our conditions, the iso-propoxy groups are fully removed and that a bisdiethyltartrate titanium complex is formed. This might reach the octahedral
388
coordination sphere by binding two of the four carboxylic groups, likely one from each DET molecule. It is therefore expected that this complex may be monomeric and highly symmetric as in 5.
5
5
The action of an alkylhydroperoxide results in the equilibrium displacement of one of the four equivalent alkoxo groups yielding only one stereoisomer 6. In the activated complex, the peroxide may become dicoordinated by removal of one of the two carboxylate ligands giving 7 (unless the heptacoordination is obtained).
,OE t
Etd
6
7
It should be remembered that the titanium complexes with oxygens ligands, as well as many other oxocomplexes of do transition metal ions, undergo very facile and fast ligand exchange and, wherever possible, conformational changes. They should be, therefore, dealt with as systems in equilibrium whose geometry is dictated by the ligand field and whose chirality is determined by the chiral ligands. On the basis of the structure of the peroxo 7 and of the generally accepted hypothesis that sulfur approaches the 0-0 bond along its axis, a model of the transition state for the S-oxidation may be formulated. It presents rather severe stereochemical limitations to the approach of the substrate and predicts an enantiomeric discrimination consistent with the results obtained.
389
In particular this model requires that one substituent at sulfur in the thioethers has to be as small as possible to enter into a rather congested area, whereas the other lays in a rather unhindered one. The Kagan's reagent should have a different structure since water is a strong ligand for Ti being also prone to give Ti-O-Ti bridged structure. Indeed evidence has been reported in favor of a dimer for the catalyst precursor [lll. The similarity of the steric requirements would suggest that the mono-bonded DET in our system and the -0-TiL, ligand play a similar role. Alternatively it could be assumed that in our catalytic system some water present as impurity in the DET is playing a role equivalent to the water added in the Kagan's reagentfl21. However this is rather unlikely. In fact, even though the two reagents have similar stereochemical behavior [131 (similar e.e. values, absolute configurations of the sulfoxides, sensitivity to substrate structure, etc) they differ in the chemical behavior at a significant extent as shown in Tables 1,2 and Figure 2. Table 1. Enantioselective oxidation of some thioethers with a) Modena-Di Furia method (substrate:Ti(i-PrO),:(+)-DET:t-BuOOH=4:1:4:2); b) Kagan's method (substrate: Ti(i-Pro),:(+)-DET:H,O:t-BuOOH= 1:1:2:1:1).
R-S-R'
R
R
Me Me CHZPh CH,Ph ~-Bu Me
p-To1 Ph p-Tol Ph p-Tol n-0ct
Asym. Oxdn.
+ -
Method a e.e.,% (config.)
Ref.
84-88 (R)
5
20 (R) 36 (R) 94 (-1
14 14 14
Method b e.e., % (config.)
Ref.
85-91 (R) 89 (R) 7 (R)
4
20 (R)
4
71 (-1
4 4
4
390
Table 2. Enantioselective oxidation of p-tolylmethylthioether with a) Modena-Di Furia method (substrate:Ti(i-PrO),:(+)-DET:t-BuOOH=4:1:4:2); b) Kagan's method (substrate: Ti(i-PrO),:(+)-DET:H20:t-BuOOH=l:l:2:l:l)
Solvent
Method a e.e.,%(config.)
Ref.
Method b e.e.,% (config.)
Ref.
CCl, CHC1, CH,Cl, ClCH,CH,Cl PhCH, CH,COCH,
53 (R) 64 (R) 80 (R) 84 (R) 56 (R) 58 (R)
14 14 14 14 14 14
4.5(S) 70 (R) 85 (R) 86 (R) 26 (R) 62 (R)
4 15 15 15 15 15
loo
I
80
i i
60
# Q
40
MDFmethod
+ Kagan
20
1
-80
-60
.
1
-40
method
'
1
..
11
-20
0
''
11
20
'
1
'
40
60
T ("C) Figure 2. Temperature effect in the enantioselective oxidation of methyl-p-tolylthioether Particularly worth of notice are the findings that in CCI, the two reagents provide methyl-p-tolylsulfoxides of opposite configuration (Table 2) and the dramatic difference in the temperature effect (Figure 2). Moreover, the role of
39 1
the water is far to be simple. It certainly does not act as a stoichiometric reagent since under the Kagan's conditions high polimers or titanyl compounds should be formed [6c]. Furthermore under our conditions, i.e. distilled solvent and DET in a ratio Ti:DET = 1:4 it is difficult to assume the presence of a so large amount of water which, in addition, should be of constant concentration throughout all the experiments. Further studies on these points are needed and some are in progress. Along this line we have pursued the study of the effect of the absolute and relative sizes of the two hydrocarbon residues linked to the sulfur atom in dialkyl or alkyl-aryl thioethers. In the series of alicyclic l,&dithioethers El61 we have shown that 1,3dithiolanes 9 are oxidized with higher enantiomeric excess than both 1,3dithianes 10 [16a] and cyclohexane condensed 1,3-dithiolane 11 [16bl, in agreement with the empirical rule of unbalanced size of the two residues bonded at sulfur.
e.e.%
9
10
11
12
76
14
39
65
We have recently obtained results which indicate that by making smaller the substituents at carbon 2 and by increasing the size of the molecule via fusion of carbons 4 and 5 in a cyclohexane ring, as in 12 [14], the conditions for obtaining rather high enantioselectivityare restored. The S-oxide of compound 12, in a chiral non racemic form, is a rather interesting synthon of formaldehyde, as shown by the extensive literature on the reactions of other homochiral sulfoxides of dithioacetals of formaldehyde 1171. The empirical "small-large" rule was also utilized in the resolution of phydroxythioethers via asymmetric oxidation t o the corresponding sulfoxides. The utilization of the P-hydroxymethylthioethers, instead of the aryl or t-butyl derivatives employed at the very beginning of our studies [18], allowed to obtain the corresponding S-oxides with reasonably high e.e. values (60-80%)1193. In some cases the enantiomeric enrichment can be rather easily increased up to the enantiomerically pure compounds by simple crystallization. These sulfoxides, after few chemical transformations, can afford other chiral compounds, i.e. epoxides or alcohols. For this class of thioethers it was observed a negative effect of the P-hydroxy group on the enantioselectivity of the oxidation. This inconvenience can be easily avoided by protection of the hydroxylic function with different groups, i.e. silyl ethers, benzoyl or acetic esters. The nature of the protecting group has little effect on the enantioselection of the process. On the other hand, it modifies the physical properties of the products and this may
392
result useful in the separation of the diastereomers and their enrichment by crystallization. Some results are reported in table 3. Table 3. Enantioselective oxidation of some P-hydroxythioethers with the Modena-Di Furia method [14,191.
R
R
Y
R'
Ph Ph Et Et
Me Me Et Et
H SiPh, SiPh, CO-o-N0,Ph
t-Bu t-Bu PhC(Me), PhC(Me),
Diast.Ratio a:b
e.e.g
e.e.b
1oo:o
18 70 65 75
68 n.d.
9O:lO 79:21 71:29
55
Another class of compounds examined is that of [l,l'-binaphthalenel-2,2'dithioethers. Different cyclic and linear thioethers were synthesized and asymmetrically oxidized [201. Some of the results obtained are reported in table 4. Table 4. Enantioselective oxidation of some [l,l'-binaphthalene]-2,2'-dithioethers with the Modena-Di Furia method.
-L
-L
-S-CH, -S-CH, -S-CH,-S-S-CH,-CH,-S-S-CH,-CH,-CH,-S-
Diast.Ratio a:b
e.e. ,%
e.e.,% b
57:46
>98 46 78 22
>98
1oo:o 1oo:o
1oo:o
a
393
As discussed above, in all these compounds the "small-large"rule is obeyed. On the other hand the experimental results reported in table 4 show how peculiar can be a "small" substituent. The e.e. values for the two diastereomeric S-oxides derived from the linear compound (entry 1) are very high (e.e.>98%). The cyclic derivatives show a maximum for the 8-membered ring (e.e.=78%), whereas the 7- and 9-membered ones afforded much smaller values. It can be worth of mention that all this cyclic derivatives yield only one diastereomer, likely that one with the oxygen in the equatorial position, as determined via xray for the 8-membered ring derivative [20b]. The results presented here as well as those already reported in the literature from several laboratories confirm the wide scope of the titanium catalyzed asymmetric oxidation of thioethers under either a theoretical or a synthetic point of view. It emerges also that a better understanding of the structure and mode of action of the reagent would be highly welcome.
REFERENCES 1. 2.
3.
4. 5 6.
7. 8. 9.
T. Katsuki and K.B. Sharpless, J. Am. Chem. SOC. No.102 (1980) 5974. a) M.G. Finn and K. B. Sharpless, "On the mechanism of Asymmetric Epoxidation with Titanium-Tartrate Catalyst" in Asymmetric Synthesis, Vol. 5, Chapt. 8, J. D. Morrison (Ed), Academic Press, New York, USA (1985); b) J.M. Hawkins; K. B. Sharpless, Tetrahedron Lett. No 28 (1987) 2825.
a) K. A. Jorgensen, R. A. Wheeler, and R. Hoffmann, J. Am. Chem. SOC. No. 109 (1987) 3240; b) P.G. Potvin, P.C.C. Kwong, and M.A. Brook, J. Chem. SOC. Chem. Commun. (1988) 773; c) E. J. Corey, J. Org. Chem., No. 55 (1990) 1693. P. Pitchen, E. Dunach, M.N. Deshmukh, and H.B. Kagan, J. Am. Chem. SOC., No. 106 (1984) 8188. F. Di Furia, G. Modena and R. Seraglia, Synthesis (19841,325. a) C.A. McAuliffe, and D.S. Barratt, "Titanium", in Comprehensive Coordination chemistry, Vol3, Chapt. 31, G. Wilkinson, R.D. Gillard, and J.A. McCleverty (Eds.), Pergamon Press, Oxford, UK, (1987); b1W.R. Russo, and W.H. Nelson, J. Am, Chem. SOC., No. 92 (1970) 1521; c) F. Babonneau, S. Doeuff, A. Leaustic, C. Sanchez, C. Cartier, and M. Verdaguer, Inorg. Chem., No. 27 (1988) 3166; d) C. Sanchez, and J. Lavage, New J. Chem., No. 14 (1990) 513. H. Mimoun, P. Chaumette, M. Mignard, L. Saussine, J. Fischer, and R. Weiss, Nouv. J. Chim. No 7 (1983) 467. A. Muller, and E. Diemann, "Thioethers" in Comprehensive Coordination Chemistry, Vol 2, Chapt. 16.2, G. Wilkinson, R.D. Gillard, and J.A. McCleverty (Eds.),Pergamon Press, Oxford, UK, (1987); S. Miyano, L.D.L. Lu, S.M. Viti, K.B. Sharpless, J. Org. Chem., No. 48 (1983) 3608.
394
10. 11.
12. 13.
14. 15.
16. 17. 18.
19. 20.
K.B. Sharpless, C.H. Behrens, T. Katsuki, A.W.M. Lee, V.S. Martin, M. Takatani, S.M. Viti, F.J. Walker, and S.S. Woodard, Pure Appl. Chem. No. 55 (1983) 589. H.B. Kagan "Asymmetric Oxidation Mediated by Organometallic Species" in Stereochemistry of Organic and Biorganic Transformations, Workshop Conferences Hoechest, Vol 17, pp. 31-48, W. Bartmann and K.B. Sharpless (Eds.), VCH, Weinheim, FRG, (1987). S.H. Zhao, 0. Samuel, and H.B. Kagan, Tetrahedron, No. 43 (1987) 5135. 0. Bortolini, F. Di Furia, G. Licini, 4nd G. Modena, "Structure-Behavior Relationship in the Enantioselective Oxidations of Sulfides" in Reviews on Heteroatom Chemistry, Vol. 1, pp. 66-79, S. Oae (Ed), Myu, Tokyo, Japan (1988). V. Conte, F. Di Furia, G. Licini, G. Modena, and G. Sbampato, unpublished results. H.B. Kagan, E. Dunach, C. Nemecek, P. Pitchen, 0. Samuel, S. Zhao, Pure Appl. Chem. No 57 (1985) 1911. a) 0. Bortolini, F. Di Furia, G. Licini, G. Modena and M. Rossi, Tetrahedron Lett., No. 27 (1986) 6257; b) F. Di Furia, G. Licini, and G. Modena, Gazz. Chim. It. (1990) 165. a) L. Colombo, C. Gennari, G, C. Scolastico, G. Guanti, E. Narisario, J. Chem SOC.Chem. Commun. (1979) 591 b) L. Colombo, C. Gennari, G. Resnati, C. Scolastico, J. Chem. SOC.Perk Trans. I (1981) 1284. 0. Bortolini, F. Di Furia, G. Licini, and G. Modena, Phosphorous and Sulfur No. 37 (1988) 171. V. Conte, F. Di Furia, G. Licini, and G. Modena, Tetrahedron Lett. No. 30 (1989) 4859. F. Di Furia, G. Licini, G. Modena and 0. De Lucchi, Tetrahedron Lett. No. 30 (1989) 2575; b) F. Di Furia, G. Licini, and G. Modena, Bull. SOC.Chim. Fr. (1990) in press.
385
Titanium-Promoted Enantioselective Oxidation of Thioethers and Synthetic Applications V. Conte, F. Di Furia, G. Licini, G. Modena and G. Sbampato Centro di Studio sui Meccanismi di Reazioni Organiche del CNR, Dipartimento di Chimica Organica dell'universita', via Marzolo, 11-35131Padova, Italy.
Abstract
The recent results of our studies on the asymmetric oxidation of alkyl and aryl thioethers by the Ti(IV)/(+)-diethyltartrate/alkylhydroperoxide reagent developed in our laboratories will be presented and their relevance in the understanding of the factors affecting the enantioselectivity of the process and in the synthesis of chiral synthons briefly discussed. A preliminary discussion on the structure of the reactive complex will also be presented.
The discovery by Sharpless of the titanium-diethyltartrate-t-butylhydroperoxide reagent for the enantioselective oxidation of allylic alcohols 111 opened a new era in the field of asymmetric synthesis. Much work and thought have been dedicated by Sharpless himself 123 and by others [31 to the understanding of the origin of the exceptional enantioselectivityof the reagent and to the development of a reasonable structure-selectivity relationship. The Sharpless catalyst precursor, where the Ti-DET ratio is 1:1, is inefficient in the asymmetric S-oxidation. However, quite effective modifications of it have been independently discovered by the Kagan's group 141 and by ourselves [51. They have, respectively,the composition Ti:DETH,O= 1:2:1 and Ti:DET=1:4. We deem it worthwhile to elaborate hrther on the structure-reactivity relationship of these systems before presenting our most recent findings in this area. The titanium alkoxides, which have the minima formula Ti(OR),, are coordinatively unsaturated species which tend, in the absence of other neutral ligands, to strongly associate either in the liquid or in the solid state [6]. As an example, Figure 1,based on x-ray data, shows a structure where each titanium atom by extensive oxobridging reaches the hexacoordination [6bl, i.e. the most
386
Figure 1. X-ray structure of Ti(OEt),. 8 = EtO frequent coordination state for Ti(IV). On the other hand, bulky, negatively charged ligands may stabilize lower coordination numbers, e.g. Ti(EtO), is present as pentacoordinate trimer in the liquid state [6dl whereas Ti(t-BuO), and Ti(t-Am), are tetrahedral monomeric species. Some titanium complexes with coordination number higher than six have also been described [2a,61. The system becomes more complicated when together with the alkoxy groups, the ligand contains other neutral centers. In this case the intramolecular coordination of such centers, e.g. the carbonyl of the carboxylate moiety in DET may successfully compete with that of external nucleophiles. Sharpless, on the basis of extensive studies [21, suggested that in his system the catalyst is the species 2, i.e. the dimer formed by association of two pentacoordinate monomers through two oxobridges. In fact, the monomer might reach the hexacoordination only by bonding the second carboxylate group at the expenses of a rather severe distortion. An alternative dimeric structure 3 has also been taken into consideration. In the latter, each Ti might easily reach the hexacoordination via bonding both carboxylate groups although other evidence indicates that the pentacoordination is maintained [2,3b].
0-i-R
a
2
387
It has been also suggested that all the oxygens in 2 are equivalent because of a fluxional equilibrium, likely uia 3. At any rate, one might argue that the titanium species tend to reach the hexacoordination wherever possible even at the expense of a corresponding entropic loss. Along this line we may anticipate some further complications arising from the reaction of the catalyst with the reagents to form the activated complex. Upon additions of the allylic alcohol, one or more of the iso-propoxy groups may be displaced without major modifications of the structure of the complex. However, when the hydroperoxide is added, some significant structural changes are expected because of the bidentate nature of the oxidant. As a matter of fact, in the transition state the hydroperoxide must be bicoordinate to the metal through both peroxo oxygens [71. As a consequence, the DET-alkoxohydroperoxotitanium complex might reach the hexacoordination without dimerization. Alternatively, the dimeric structure might be preserved, by removal of the carboxylate ligand. Although, it is not easy to distinguish between the two alternatives presented above, it may be u s e l l to recall that Corey [3cl has recently suggested that the coordination of the hydroperoxide has a depolimerizing effect on the titanium complex. Whether the subsequent dissociation into ion pairs, as suggested, or two neutrals takes place is not relevant in this context. Independently of the structure of the activated complex in the Sharpless oxidation, either monomeric or dimeric, it is nevertheless possible to propose a rationale for the modifications of the reagent itself which allow the enantioselective oxidation of thioethers. In fact, since such substrates are too weak ligands toward titanium 181 to behave as the allylic alcohols do, they will not displace the iso-propoxygroups in the titanium catalyst. Such groups will be displaced by the hydroperoxide leading either to two diastereoisomeric monoperoxides o r to a diperoxide with the two peroxo groups in diastereotopic positions. It is not surprising that either the mixture of the two monoperoxides or the diperoxide are not efficient enantioselective oxidants. Indeed the Sharpless reagent oxidizes alkyl or aryl thioethers without any significant enantioselectivity, even though it can asymmetrically oxidize p-hydroxy tertiary amines to the corresponding N-oxides [9] and, less efficiently, phydroxythioethers [lo]. This is likely due to the fact that such substrates may act, in some way, like the allylic alcohols as far as the coordination to the metal is concerned. The two modifications of the Sharpless reagent proposed by Kagan (addition of one equivalent of water) [41 and by ourselves (large excess of DET) [5], independently of how they have been conceived, have in common the presence of reagents able to displace either one or both iso-propoxy ligands. This eliminates the problem mentioned above of forming peroxocomplexes rather inefficient as asymmetric oxidants. Even in the absence of direct physical evidence, we may argue that under our conditions, the iso-propoxy groups are fully removed and that a bisdiethyltartrate titanium complex is formed. This might reach the octahedral
388
coordination sphere by binding two of the four carboxylic groups, likely one from each DET molecule. It is therefore expected that this complex may be monomeric and highly symmetric as in 5.
5
5
The action of an alkylhydroperoxide results in the equilibrium displacement of one of the four equivalent alkoxo groups yielding only one stereoisomer 6. In the activated complex, the peroxide may become dicoordinated by removal of one of the two carboxylate ligands giving 7 (unless the heptacoordination is obtained).
,OE t
Etd
6
7
It should be remembered that the titanium complexes with oxygens ligands, as well as many other oxocomplexes of do transition metal ions, undergo very facile and fast ligand exchange and, wherever possible, conformational changes. They should be, therefore, dealt with as systems in equilibrium whose geometry is dictated by the ligand field and whose chirality is determined by the chiral ligands. On the basis of the structure of the peroxo 7 and of the generally accepted hypothesis that sulfur approaches the 0-0 bond along its axis, a model of the transition state for the S-oxidation may be formulated. It presents rather severe stereochemical limitations to the approach of the substrate and predicts an enantiomeric discrimination consistent with the results obtained.
389
In particular this model requires that one substituent at sulfur in the thioethers has to be as small as possible to enter into a rather congested area, whereas the other lays in a rather unhindered one. The Kagan's reagent should have a different structure since water is a strong ligand for Ti being also prone to give Ti-O-Ti bridged structure. Indeed evidence has been reported in favor of a dimer for the catalyst precursor [lll. The similarity of the steric requirements would suggest that the mono-bonded DET in our system and the -0-TiL, ligand play a similar role. Alternatively it could be assumed that in our catalytic system some water present as impurity in the DET is playing a role equivalent to the water added in the Kagan's reagentfl21. However this is rather unlikely. In fact, even though the two reagents have similar stereochemical behavior [131 (similar e.e. values, absolute configurations of the sulfoxides, sensitivity to substrate structure, etc) they differ in the chemical behavior at a significant extent as shown in Tables 1,2 and Figure 2. Table 1. Enantioselective oxidation of some thioethers with a) Modena-Di Furia method (substrate:Ti(i-PrO),:(+)-DET:t-BuOOH=4:1:4:2); b) Kagan's method (substrate: Ti(i-Pro),:(+)-DET:H,O:t-BuOOH= 1:1:2:1:1).
R-S-R'
R
R
Me Me CHZPh CH,Ph ~-Bu Me
p-To1 Ph p-Tol Ph p-Tol n-0ct
Asym. Oxdn.
+ -
Method a e.e.,% (config.)
Ref.
84-88 (R)
5
20 (R) 36 (R) 94 (-1
14 14 14
Method b e.e., % (config.)
Ref.
85-91 (R) 89 (R) 7 (R)
4
20 (R)
4
71 (-1
4 4
4
390
Table 2. Enantioselective oxidation of p-tolylmethylthioether with a) Modena-Di Furia method (substrate:Ti(i-PrO),:(+)-DET:t-BuOOH=4:1:4:2); b) Kagan's method (substrate: Ti(i-PrO),:(+)-DET:H20:t-BuOOH=l:l:2:l:l)
Solvent
Method a e.e.,%(config.)
Ref.
Method b e.e.,% (config.)
Ref.
CCl, CHC1, CH,Cl, ClCH,CH,Cl PhCH, CH,COCH,
53 (R) 64 (R) 80 (R) 84 (R) 56 (R) 58 (R)
14 14 14 14 14 14
4.5(S) 70 (R) 85 (R) 86 (R) 26 (R) 62 (R)
4 15 15 15 15 15
loo
I
80
i i
60
# Q
40
MDFmethod
+ Kagan
20
1
-80
-60
.
1
-40
method
'
1
..
11
-20
0
''
11
20
'
1
'
40
60
T ("C) Figure 2. Temperature effect in the enantioselective oxidation of methyl-p-tolylthioether Particularly worth of notice are the findings that in CCI, the two reagents provide methyl-p-tolylsulfoxides of opposite configuration (Table 2) and the dramatic difference in the temperature effect (Figure 2). Moreover, the role of
39 1
the water is far to be simple. It certainly does not act as a stoichiometric reagent since under the Kagan's conditions high polimers or titanyl compounds should be formed [6c]. Furthermore under our conditions, i.e. distilled solvent and DET in a ratio Ti:DET = 1:4 it is difficult to assume the presence of a so large amount of water which, in addition, should be of constant concentration throughout all the experiments. Further studies on these points are needed and some are in progress. Along this line we have pursued the study of the effect of the absolute and relative sizes of the two hydrocarbon residues linked to the sulfur atom in dialkyl or alkyl-aryl thioethers. In the series of alicyclic l,&dithioethers El61 we have shown that 1,3dithiolanes 9 are oxidized with higher enantiomeric excess than both 1,3dithianes 10 [16a] and cyclohexane condensed 1,3-dithiolane 11 [16bl, in agreement with the empirical rule of unbalanced size of the two residues bonded at sulfur.
e.e.%
9
10
11
12
76
14
39
65
We have recently obtained results which indicate that by making smaller the substituents at carbon 2 and by increasing the size of the molecule via fusion of carbons 4 and 5 in a cyclohexane ring, as in 12 [14], the conditions for obtaining rather high enantioselectivityare restored. The S-oxide of compound 12, in a chiral non racemic form, is a rather interesting synthon of formaldehyde, as shown by the extensive literature on the reactions of other homochiral sulfoxides of dithioacetals of formaldehyde 1171. The empirical "small-large" rule was also utilized in the resolution of phydroxythioethers via asymmetric oxidation t o the corresponding sulfoxides. The utilization of the P-hydroxymethylthioethers, instead of the aryl or t-butyl derivatives employed at the very beginning of our studies [18], allowed to obtain the corresponding S-oxides with reasonably high e.e. values (60-80%)1193. In some cases the enantiomeric enrichment can be rather easily increased up to the enantiomerically pure compounds by simple crystallization. These sulfoxides, after few chemical transformations, can afford other chiral compounds, i.e. epoxides or alcohols. For this class of thioethers it was observed a negative effect of the P-hydroxy group on the enantioselectivity of the oxidation. This inconvenience can be easily avoided by protection of the hydroxylic function with different groups, i.e. silyl ethers, benzoyl or acetic esters. The nature of the protecting group has little effect on the enantioselection of the process. On the other hand, it modifies the physical properties of the products and this may
392
result useful in the separation of the diastereomers and their enrichment by crystallization. Some results are reported in table 3. Table 3. Enantioselective oxidation of some P-hydroxythioethers with the Modena-Di Furia method [14,191.
R
R
Y
R'
Ph Ph Et Et
Me Me Et Et
H SiPh, SiPh, CO-o-N0,Ph
t-Bu t-Bu PhC(Me), PhC(Me),
Diast.Ratio a:b
e.e.g
e.e.b
1oo:o
18 70 65 75
68 n.d.
9O:lO 79:21 71:29
55
Another class of compounds examined is that of [l,l'-binaphthalenel-2,2'dithioethers. Different cyclic and linear thioethers were synthesized and asymmetrically oxidized [201. Some of the results obtained are reported in table 4. Table 4. Enantioselective oxidation of some [l,l'-binaphthalene]-2,2'-dithioethers with the Modena-Di Furia method.
-L
-L
-S-CH, -S-CH, -S-CH,-S-S-CH,-CH,-S-S-CH,-CH,-CH,-S-
Diast.Ratio a:b
e.e. ,%
e.e.,% b
57:46
>98 46 78 22
>98
1oo:o 1oo:o
1oo:o
a
393
As discussed above, in all these compounds the "small-large"rule is obeyed. On the other hand the experimental results reported in table 4 show how peculiar can be a "small" substituent. The e.e. values for the two diastereomeric S-oxides derived from the linear compound (entry 1) are very high (e.e.>98%). The cyclic derivatives show a maximum for the 8-membered ring (e.e.=78%), whereas the 7- and 9-membered ones afforded much smaller values. It can be worth of mention that all this cyclic derivatives yield only one diastereomer, likely that one with the oxygen in the equatorial position, as determined via xray for the 8-membered ring derivative [20b]. The results presented here as well as those already reported in the literature from several laboratories confirm the wide scope of the titanium catalyzed asymmetric oxidation of thioethers under either a theoretical or a synthetic point of view. It emerges also that a better understanding of the structure and mode of action of the reagent would be highly welcome.
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